Our long-term goal is to develop advanced materials for neural interfaces which will seamlessly assimilate within the neural tissue to facilitate sustained molecular level connections with individual neurons. To accomplish this goal, the materials must mediate the inflammatory response and interact with the normal cellular machinery. In order to quench the neurodegenerative inflammatory response to cortical electrodes, the objective of this project is to first develop an improved understanding of the inflammatory cascade, in order to later engineer more specific interventions. The primary hypothesis of this proposal is that selective ablation of microglia/macrophage cells at the cortical tissue - electrode interface will attenuate the neurodegenerative effects of the chronic inflammatory response. Furthermore, it is also hypothesized that inflammation at the cortical tissue-electrode interface can be imaged in real-time using protease selective Near Infrared Fluorescent (NIRF) imaging probes to assess the cortical tissue-electrode interface, for the first time in living animals. This research project is divided into three distinct aims. The first will engineer a viral vector to specifically cause the programmed cell death of microglial cells, a key contributor in the inflammatory response to this class of electrode. A unique attribute of the design of our virus, is that a chemical initiator must be provided, secondary to the genetic material, to initiate cell ablation. This allows the research team to investigate various stages of the inflammatory cascade with one concise modality. Further, chemical modifications to traditional penetrating intracortical microelectrodes will also be explored, with the focus of promoting biomaterial-mediated gene transfer of the new virus to microglial cells at the electrode-tissue interface. The completion of this aim will provide a comprehensive strategy to selectively ablate microglial cells only at the electrode-tissue interface, allowing for as much unaffected tissue as possible, to maintain tissue homeostasis and repair. The second aim to this project will be in the validation of extending the application of molecular imaging techniques to the investigation of inflammation at the cortical tissue-electrode interface. Such molecular probes have been readily employed to study cancer growth and inflammatory disease due to their ability to detect precise biochemical events in the inflammatory cascade. Specifically, reactive microglial and macrophages over express a class of proteases. The probes used here bind exclusively to these proteases and fluoresce to allow for quantification of the protease - thus an indirect measurement of inflammation. The technique will first be validated through topical administration to excised brains having previously received an implanted electrode. Then, the molecular probes will be delivered intravenously to live animals to ensure the ability of the molecules to pass the blood-brain-barrier and localize at the electrode-tissue interface. The final aim of this project will be to demonstrate that both techniques can be applied to living animals (mice) to gain a real-time, molecular-level understanding of the complex biochemical pathways which are at play at the cortical tissue-electrode interface. This research team will, for the first time, be able to investigate such interactions in real-time, thus developing a responsive system for the investigation of future therapeutic interventions; while at the same time gaining an understanding for the role microglial cells play in device failure. Once the primary objectives of this proposal have been accomplished, we will then begin to investigate the effects of microglia ablation on the ability to maintain chronic neural recordings. PUBLIC HEALTH RELEVANCE: Project Narrative: It has become a reality for prosthetic devices to be controlled by intracortical electrodes which record one's 'thoughts.' Such devices could restore function to patients with motor deficiencies including individuals who have suffered from spinal cord injuries (~15,000/yr in the US) or stroke (750,000/yr in the US); of which a significant population are veterans. Unfortunately, this technology is not readily available to our veterans due to the lack of reliability of the recordings, regardless of the type of electrode used. While several methods have been investigated to increase the longevity of electrodes implanted in the brain, this technology has rarely applied to human patients due to an incomplete understanding of the mechanisms that lead to the device failure, largely attributed to the inflammatory response. Therefore a more robust understanding of the inflammatory response at the device-tissue interface promises to expedite the development of methods to attenuate the response, and translate the powerful technology into clinical solutions for our veterans.